Thyroid cancer is the most common endocrine malignancy with a rapid rising incidence in recent years, which is largely attributable to the increased diagnosis of thyroid nodules. There are several areas in thyroid tumor medicine in which efficiency and effectiveness of patient management are limited with the current standard approaches. For example, the widely used fine needle aspiration biopsy (FNAB) for thyroid nodule evaluation often yields indeterminate cytological findings, leading to unnecessary thyroid surgery; the standard serum thyroglobulin (Tg) testing to monitor thyroid cancer recurrence is often hampered by the presence of autoantibodies against Tg in the serum; and the current prognostic evaluation of thyroid cancer using clinicopathological criteria is often uncertain, particularly preoperatively. Novel thyroid diagnostic and prognostic molecular markers, if available, could help circumvent these clinical obstacles. As aberrant DNA methylation patterns are often specifically associated with human cancers, we hypothesize that unique DNA methylation patterns or alterations also exist in thyroid cancer and could be used as reliable molecular markers for this cancer. To test this hypothesis, in the present project we propose to use a recently developed powerful 450K DNA methylation microarray system to perform genome-wide search for aberrant DNA methylation alterations in thyroid tumors to identify panels of most prominent DNA methylation markers that have the highest diagnostic and prognostic potential with the best specificities and sensitivities for thyroid cancer. We will then test them on FNAB and serum specimens collected from thyroid tumor patients with the goal to establish novel clinical diagnostic and prognostic molecular tests for the management of thyroid nodules and thyroid cancer. This project represents a novel approach using a powerful experimental system to identifying DNA methylation molecular markers for thyroid cancer, which is expected to have a significant impact on the current practice of thyroid tumor medicine. The research team and their laboratory are well experienced and equipped with both technical expertise and thyroid tumor patient specimens required to successfully pursue the proposed studies.